Processes for the preparation of oxo-oxazoline or alloamino acid derivatives

ABSTRACT

A method for producing a compound represented by the general formula (I-A) or the general formula (I-B), comprising the following step:  
                 
 
     wherein R 1  is an optionally substituted lower alkyl, and the like; R 2  is a lower alkyl or an optionally substituted aralkyl, and the like; R 3  is a lower alkyl, characterized in that a compound represented by the general formula (II-A) or the general formula(II-B) is treated with thionyl chloride.

TECHNICAL FIELD

[0001] The present invention relates to a method for producingoxo-oxazoline derivatives using a simple and inexpensive method.

BACKGROUND ART

[0002] Oxo-oxazoline derivatives are critical intermediates forcompounds (WO98/08867) which are TRH (thyrotropin releasing hormone)derivatives represented by the following general formula (VIII):

[0003] wherein R^(A) is a hydrogen atom or optionally substituted loweralkyl: Y is an optionally substituted alkyl.

[0004] Further, compounds represented by the following general formulas(III-A), (III-B), (IV-A), or (IV-B):

[0005] wherein R¹ is an optionally substituted lower alkyl, anoptionally substituted aryl, an alkynyl, or an optionally substitutedheteroaryl, and derivatives thereof, are useful as tools forcombinatorial chemistry.

[0006] Conventionally, as a method for producing oxo-oxazolinederivatives having a lower alkyloxycarbonyl group or a carboxyl group, amethod of cyclizing a starting material while retaining itsstereochemistry, and a method using cyclization reaction withoutreference to stereoselectivity are known.

[0007] An example of the method of cyclizing a starting material whileretaining its stereochemistry is the following:

[0008] (Tetrahedron, 48, 2507, 1992). In this reaction, L-allo-threonineused as a starting material is allowed to react with phosgene andpotassium hydroxide in toluene at 0° C. for one hour, thereby obtaininga cyclized product which retains its stereochemisty. Unfortunately, thismethod encounters a problem in industrialization since the methodemploys L-allo-threonine which is more expensive than its natural type,and phosgene which is toxic to the human body.

[0009] An example of the cyclization method without reference tostereoselectivity is the following:

[0010] (Japanese Laid-Open Publication No. 60-34955). In this reaction,a starting material is allowed to react with potassium carbonate inwater at 60° C. for 1.5 hours to obtain a cyclized product. It isbelieved that the stereochemistry of the material is maintained in viewof the mechanism of this method. Therefore, it is considered thatallo-threonine needs to be used as a starting material in order toobtain a cis-form cyclized product.

[0011] Although a resultant cyclized product is an oxo-oxazolinederivative which does not have a lower alkyloxycarbonyl group or acarboxyl group, the following method is known:

[0012] (Bull. Chem. Soc. Japan., 44, 2515, 1971). In this reaction, astarting material is allowed to react in thionyl chloride at 60° C. for24 hours without solvent, thereby obtaining a cyclized product at ayield of 65%. In this method, similar to the method of the presentinvention, the position of an ethyl group is inverted after thereaction. However, the starting material is not an amino acidderivative, and the relationship between the amino group and thehydroxyl group of the starting material is different from that of astarting material used in the method of the present invention. Moreover,since the reaction is conducted in thionyl chloride, the yield is as lowas 65%.

[0013] Similar to the method of the present invention, a cyclizationreaction with inversion is known:

[0014] (Heterocycl. Commun., 2, 55, 1996). An example in whichtrifluoroacetic anydride is used in the first step is disclosed.Although in the method of the present invention, the yield of acyclization reaction is as high as 83%, the yield of the cyclizationreaction disclosed in the above-described publication is as low as 40%in both a method using tosyl chloride and a method using trifluoroaceticanydride. Moreover, the method of the present invention is superior inregard to simplicity of reaction.

DISCLOSURE OF THE INVENTION

[0015] The objective of the present invention is to provide a method forproducing oxo-oxazoline derivatives in a simple, inexpensive andstereoselective manner. The oxo-oxazoline derivatives are useful asintermediates for pharmaceuticals and tools for combinatorial chemistry.Moreover, the oxo-oxazoline derivatives in an open-circular form arealso useful as tools for combinatorial chemistry.

[0016] The inventors found a method for producing oxo-oxazolinederivatives in a stereoselective manner, which is suitable forlarge-scale synthesis.

[0017] That is, the present invention relates to

[0018] I) A method for the production of a compound represented by ageneral formula (I-A) or a general formula (I-B), comprising the step oftreating a compound represented by a general formula (II-A) or a generalformula (II-B) with thionyl chloride as follows:

[0019] wherein R¹ is an optionally substituted lower alkyl, anoptionally substituted aryl, an alkynyl, or an optionally substitutedheteroaryl; R² is a lower alkyl, an optionally substituted aralkyl, oran optionally substituted heteroarylalkyl; and R³ is a lower alkyl.

[0020] More specifically, the present invention relates to following II)to X).

[0021] II) A method for the production according to I), wherein thecompound represented by the general formula (II-A) or the generalformula (II-B) is allowed to react with 1.0 to 5.0 equivalents ofthionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, oracetonitrile at 30° C. to reflux temperature.

[0022] III) A method for the production according to I), wherein thecompound represented by the general formula (II-A) or the generalformula (II-B) is allowed to react with 1.0 to 3.0 equivalents ofthionyl chloride in a solvent of toluene, ethyl acetate, cyclohexane, oracetonitrile at 60° C. to 80° C.

[0023] IV) A method for the production of a compound represented by ageneral formula (III-A) or a general formula (III-B), comprising thestep of subjecting a compound represented by a general formula (I-A) ora general formula (I-B) obtained by a method according to any of I) toIII) to a hydrolysis as follows:

[0024] wherein R¹ and R³ are as described above.

[0025] V) A method for the production of a compound represented by ageneral formula (IV-A) or a general formula (IV-B), comprising the stepof subjecting a compound represented by a general formula (III-A) or ageneral formula (III-B) obtained by a method according to IV) to ahydrolysis as follows:

[0026] wherein R¹ is as described above.

[0027] VI) A method for the production of a compound represented by ageneral formula (I-A) or a general formula (I-B), comprising the step ofprotecting the amino group of a compound represented by a generalformula (V-A) or a general formula (V-B) with R²OC(═O)—, wherein R² isas described above, esterifying the carboxyl group thereof, and treatingwith thionyl chloride as follows:

[0028] wherein R¹ and R³ are as described above.

[0029] VII) A method for production of a compound represented by ageneral formula (VI):

[0030] wherein R¹ is as described above, and Y is an optionallysubstituted alkyl, comprising the step of subjecting a compoundrepresented by a general formula (III-A) or a general formula (III-B)obtained by a method according to IV) to a peptide bond formation.

[0031] VIII) A method for the production according to IV), wherein R¹ isphenyl, 5-imidazolyl, methyl, isopropyl, ethynyl, or 1-propynyl.

[0032] IX) A method for the production according to IV), wherein R² is alower alkyl, an aralkyl, or a heteroarylalkyl.

[0033] X) A method for the production according to IV), wherein R² is anaralkyl.

[0034] XI) A method for the production according to IV), wherein R¹ ismethyl and R² is benzyl.

[0035] “Halogen” as used herein refers to fluorine, chlorine, bromine,and iodine. Chlorine and bromine are preferable.

[0036] The term “lower alkyl” as herein used alone or in combinationwith other words comprises C₁-C₆ straight chained or branched alkyl.Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, and t-butyl, and the like. Methyl andethyl are preferable.

[0037] “Alkynyl” as used herein comprises C₂-C₈ straight or branchedchain monovalent hydrocarbon group having one or two or more triplebonds. The alkynyl may have a double bond. Examples of the alkynylinclude ethynyl, 1-propynyl, 2-propynyl, 6-heptynyl, 7-octynyl,and8-nonyl, and the like. Ethynyl and 1-propynyl are preferable.

[0038] The term “aryl” as herein used alone or in combination with otherwords comprises a monocyclic or condensed ring aromatic hydrocarbon.Examples of the aryl include phenyl, 1-naphthyl, 2-naphthyl, anthryl,and the like.

[0039] “Aralkyl” as used herein comprises the above-described “loweralkyl” substituted with the above-described “aryl” where thesubstitution may be carried out at any possible position. Examples ofthe aralkyl include benzyl, phenylethyl (e.g., 2-phenylethyl, and thelike), phenylpropyl (e.g., 3-phenylpropyl, and the like), naphthylmethyl(e.g., 1-naphthylmethyl, 2-naphthylmethyl, and the like), andanthrylmethyl (e.g., 9-anthrylmethyl, and the like), and the like.Benzyl, and the like are preferable.

[0040] “Heteroaryl” as used herein comprises a 5 to 6-membered aromaticring including one or more atoms arbitrarily selected from oxygen atom,sulfur atom or nitrogen atom within the ring. Heteroaryl may be fusedwith cycloalkyl, aryl, or other heteroaryl at any possible position.Regardless whether the heteroaryl is monocyclic or fused cyclic, theheteroaryl can bind at any possible position.

[0041] Examples of the heteroaryl include pyrrolyl (e.g., 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g.,2-thienyl, 3-thienyl), imidazolyl (e.g., 4-imidazolyl, 5-imidazolyl),pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g.,3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g.,2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl,3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g.,2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl),tetrazolyl (e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl),thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g.,2-indolizinyl, 6-indolizinyl), isoindolyl (e.g., 2-isoindolyl), indolyl(e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl),purinyl (e.g., 8-purinyl), quinolizinyl (e.g., 2-quinolizinyl),isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl,5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g.,2-naphthyridinyl), quinolanyl (e.g.,2-quinolanyl), quinazolinyl (e.g.,2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g.,2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 4-carbazolyl),phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl(e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g.,1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g.,2-benzimidazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), benzoxazolyl(e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl),benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g.,2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), andbenzothienyl(e.g.,2-benzothienyl). As “heteroaryl” of R¹, imidazolyl andthe like are preferable.

[0042] “Heteroarylalkyl” as used herein comprises the above-described“lower alkyl” substituted with the above-described “heteroaryl”, wheresuch a substitution may be carried out at any possible position.

[0043] “Optionally substituted lower alkyl” at R¹ as used hereincomprises the above-described “lower alkyl” which may have one or moresubstituents at any possible positions, such as hydroxy, alkyloxy (e.g.,methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and. ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentinclude lower alkyloxy, halogen, and the like. Examples of the“optionally substituted lower alkyl” include methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, andtrifluoromethyl, and the like. An unsubstituted lower alkyl ispreferable.

[0044] “Optionally substituted alkyl” at Y as used herein comprises theabove-described “alkyl” which may have one or more substituents at anypossible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), carboxy, carbamoyl,alkyloxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl),aryloxycarbonyl (e.g., phenyloxycarbonyl), nitro, cyano, SO_(p)R^(A) isan integer of 1 to 3, R^(A) is hydrogen or alkyl), PO(OH)₂ or P(O)OHwhich may be substituted with alkyl, substituted or unsubstituted amino(e.g., methylamino, dimethyl amino, and carbamoyl amino), optionallysubstituted aryl (e.g., phenyl and tolyl), optionally substitutedheteroaryl, optionally substituted nonaromatic heterocyclic group,aryloxy, acyloxy, acyloxycarbonyl, alkylcarbonyl, nonaromaticheterocyclic carbonyl, heterocyclic imino, hydrazino, hydroxyamino,alkyloxyamino, formyl, and the like. Examples of the “optionallysubstituted alkyl” include methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl,benzyl, hydroxymethyl, tert-butylcarbonyloxymethyl, morpholinomethyl,piperidinomethyl, N-methyl-1-piperazinylmethyl, ethylcarbonylmethyl, andmorpholinocarbonylmethyl, acetyloxymethyl, and the like. Anunsubstituted alkyl is preferable, particularly methyl.

[0045] “Optionally substituted aryl” as used herein comprises theabove-described “aryl” which may have one or more substituents at anypossible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentinclude lower alkyloxy and halogen, and the like. Examples of the“optionally substituted aryl” include phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, and the like. An unsubstituted aryl ispreferable.

[0046] “Optionally substituted heteroaryl” as used herein comprises theabove-described “heteroaryl” which may have one or more substituents atany possible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentsinclude lower alkyloxy, halogen, and the like. Examples of the“optionally substituted heteroaryl” include 2-chloroimidazole-5-yl,4-chloroimidazole-5-yl, and the like. An unsubstituted heteroaryl ispreferable.

[0047] “Optionally substituted aralkyl” as used herein comprises theabove-described “aralkyl” which may have one or more substituents at anypossible positions, such as hydroxy, alkyloxy (e.g., methoxy andethoxy), mercapto, alkylthio (e.g., methylthio) , cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), halogen (e.g.,fluorine, chlorine, bromine, and iodine), alkyloxycarbonyl (e.g.,methyloxycarbonyl and ethyloxycarbonyl), aryloxycarbonyl (e.g.,phenyloxycarbonyl), nitro, cyano, aryloxy, acyloxy, acyloxycarbonyl,alkylcarbonyl, and the like. Preferable examples of the substituentsinclude lower alkyloxy, halogen, and the like. Examples of the“optionally substituted aralkyl” include furyl, thienyl, pyridyl,5-chlorofuryl, 5-thienyl, 3-chloropyridyl, and the like. Anunsubstituted aralkyl is preferable.

BEST MODE FOR CARRYING OUT THE INVENTION

[0048] The production method of the present invention will be describedin detail in which a starting material is one optically activesubstance. When the other material is used, similar reactions can becarried out. When a starting material has a substituent which is anobstacle to a reaction in first to sixth steps shown below, the startingmaterial may be protected in advance in accordance with a methoddescribed in Protective Groups in Organic Synthesis, Theodora W Green(John Wiley & Sons), and the like, and deprotected in an appropriatestage.

[0049] wherein R¹, R², R³, and Y are as described above.

[0050] (First Step)

[0051] In the first step, R²OC(═O)-Hal, wherein Hal is halogen,[R²OC(═O)]₂O, and the like are caused to react with a compoundrepresented by a general formula (V-A) to obtain a compound (VII-A) inwhich an amino group is protected by R²OC(═O)—. This step can be carriedout in accordance with a method described in Protective Groups inOrganic Synthesis, Theodora W Green (John Wiley & Sons), and the like.

[0052] For example, a compound represented by a general formula (V-A) iscaused to react with 1.0 equivalent to 3.0 equivalents, preferably 1.0equivalent to 1.5 equivalents, of R²OC(═O)-Hal, wherein Hal is halogen,and 2.0 equivalents to 6.0 equivalents, preferably 2.0 equivalents to3.0equivalents, of an organic base (e.g., triethylamine, and the like) oran inorganic base (e.g., sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, and the like), in a mixed solvent, such aswater-toluene, water-dioxane, water-acetone, and the like, or a solvent,such as water, dioxane, and the like at −20° C. to 50° C., preferably 0°C. to 20° C. for 0.5 to 3 hours to obtain a compound represented by ageneral formula (VII-A).

[0053] In the above-described IV), “step of protecting an amino groupwith R²OC(═O)— refers to this first step.

[0054] (Second Step)

[0055] In the second step, the carboxyl group of a compound representedby a general formula (VII-A) is esterified to obtain a compoundrepresented by a general formula (II-A). This step can be carried out bya commonly used esterification.

[0056] For example, a compound represented by the general formula(VII-A) is dissolved in a solvent, such as methanol, ethanol, isopropylalcohol, and the like, and allowed to react with 1 equivalent to 5equivalents, preferably 1 equivalent to2 equivalents, of a halogenatingagent, such as thionyl chloride, hydrochloric acid, phosphorusoxychloride, and the like, at −20° C. to 50° C., preferably 0OC to 25°C., one hour to 24 hours, preferably one hour to 3 hours to obtain acompound represented by a general formula (II-A).

[0057] In the above-described IV), “step of esterifying a carboxylgroup” refers to this second step.

[0058] (Third Step)

[0059] The third step is a cyclization reaction in which thestereochemistry of R¹ is reversed.

[0060] For example, a compound represented by a general formula (I-A)can be obtained in accordance with 1) to 3) described below. 1) acompound represented by a general formula (II-A) is dissolved in asolvent, such as toluene, ethyl acetate, cyclohexane, acetonitrile, andthe like, preferably toluene. The amount of the solvent is preferably 1V to 50 V, particularly 1 V to 10 V, where use of 1 ml of a solvent withrespect to 1 g of a starting material is referred to as 1 V. 2) 1.0equivalent to 20 equivalents, preferably 1.0 equivalent to 2.0equivalents, of thionyl chloride are added at 25° C. to 80° C.,preferably 25° C. to 50° C. Thionyl chloride can be used as a solvent.3) The reaction solution is stirred at 25° C. to 80° C., preferably 60°C. to 800° C., for 5 hours to 48 hours, preferably 6 hours to 12 hours.

[0061] In this reaction, the closer the equivalent value of thionylchloride is to 1.0 and the higher the “V” value of the amount of thesolvent, the proportion of the cis-form of the intended compound wasincreased (the proportion of the trans-form was decreased).

[0062] The yield of the total compounds of cis-form and trans-form isnot substantially affected by the equivalent value of thionyl chlorideand the amount of the solvent.

[0063] In the above-described IV), “step of treating with thionylchloride” refers to this third step.

[0064] (Fourth Step)

[0065] In the fourth step, an ester compound represented by the generalformula (I-A) is hydrolyzed to carboxylic acid. This step can be carriedout by a commonly used hydrolysis.

[0066] For example, a compound represented by the general formula (I-A)is dissolved in a solvent, such as water, and the like, and 0.1equivalent to 10 equivalents, preferably 1 equivalent to 5 equivalents,of acid (e.g., hydrochloric acid, sulfuric acid, and the like) are addedto the solution at 0° C. to 100° C., preferably 25° C. to 80° C. Theresultant solution is allowed to react at 25° C. to 100° C., preferably50° C. to 80° C. for 1 hour to 5 hours to obtain a compound representedby a general formula (III-A). This step can be carried out under basicconditions.

[0067] (Fifth Step)

[0068] In the fifth step, a compound represented by the general formula(III-A) is hydrolyzed to obtain allo-amino acid derivatives representedby a general formula (IV-A).

[0069] For example, a compound represented by the general formula(III-A) is dissolved in a solvent, such as water, and 0.1 equivalent to20 equivalents, preferably 1 equivalent to 10 equivalents, of acid (e.g., hydrochloric acid,. sulfuric acid, and the like) are added to thesolution at 0° C. to 100° C., preferably 25° C. to 80° C. The resultantsolution is allowed to react at 25° C. to 100° C., preferably 80° C. to100° C. for 1 hour to 48 hours to obtain a compound represented by thegeneral formula (IV-A).

[0070] (Sixth Step) (Peptide Bond Formation)

[0071] Three amino acid derivatives are subjected to two peptide bondformation to synthesize a compound (VI) (WO98/08867). A compoundrepresented by the general formula (I-A) obtained by the above-describedmethod is used to synthesize the compound (VI) in the following twomethods (method A and method B).

[0072] wherein R⁴ is the protecting group of a carboxyl group, R⁵ is theprotecting group of an amino group, and R¹ and Y are as described above.

[0073] Method A—First Step

[0074] The carboxyl group of 3-(4-thiazole)alanine synthesized inaccordance with a method described in Synth. Commun., 20, 22, 3507(1990) and Chem. Pharm. Bull., 38, 1, 103 (1990), is protected as anester, such as methyl ester, benzyl- ester, t-butyl ester,diphenylmethyl ester, and the like, resulting in a compound representedby a general formula (VIII). This compound and a compound represented bythe general formula (III-A) are subjected to a peptide bond formation.

[0075] When the carboxyl group is protected as diphenylmethyl ester, theprotecting reaction can be carried out as follows. 3-(4-thiazole)alanineis dissolved in a mixed solvent of an alcohol solvent, such as methanol,ethanol, and the like and a solvent, such as tetrahydrofuran, dioxane,and the like. 1 to 3 equivalents, preferably 1 to 2 equivalents, ofdiphenyl diazomethane are added to the solution at 0 to 50° C.,preferably 20 to 40° C. for 10 minutes to 1 hour, preferably 20 to 40minutes. The resultant solution is allowed to react at the sametemperature for 30 minutes to 3 hours, preferably 1 to 2 hours whilebeing stirred.

[0076] The peptide bond formation is described in “Peputido Gosei[Peptide Synthesis]” (Nobuo Izumiya, Maruzen), and the like, and can becarried out by such a commonly used peptide bond formation method.

[0077] As commonly used peptide bond formation methods, a methodemploying a condensing agent, such as N,N-dicyclohexylcarbodiimide(DCC), and the like, an azide method, an acid chloride method, an acidanhydride method, an active ester method, and the like. When a startingmaterial has a substituent (amino, carboxy, hydroxyl, and the like)which is an obstacle to the peptide formation, the substituent can beprotected in advance in accordance with a method described in ProtectiveGroups in Organic Synthesis, Theodora W. Green (John Wiley & Sons), andthe like, and the protecting group is removed at a desired stage.

[0078] A compound represented by the general formula (VIII) and acompound represented by the general formula (III-A) are dissolved in asolvent, such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile,and the like. An N,N-dimethylformamide solution of a base, such astriethylamine, and the like, and dicyclohexylcarbodiimide (DCC), isadded to that solution at −10 to 10° C., preferably in ice bath.1-hydroxybenzotriazole may be added. The resultant solution is stirredat 10 to 50° C., preferably 20 to 30° C., for one hour to one day,preferably 5 to 10 hours, followed by typical subsequent processes.Thus, a compound represented by a general formula (IX) can be obtained.

[0079] Method A—Second Step

[0080] A deprotecting reaction can be carried out by a commonly useddeprotecting reaction (Protective Groups in Organic Synthesis, TheodoraW. Green (John Wiley & Sons)). For example, when R⁴ is diphenylmethyl, acompound represented by a general formula (IX) can be added to anisoleand trifluoro acetic acid at −10 to 10° C., preferably in ice bath. Themixture is stirred at the same temperature for 5 to 30 minutes,preferably 10 to 20 minutes. After the mixture is warmed to 20 to 40°C., the mixture can be stirred for 1 to 4 hours, preferably 2 to 3hours.

[0081] The resultant deprotected substance can be reacted with apyrrolidine derivative synthesized by a method described in Tetrahedron,27, 2599 (1971) through a peptide bond formation similar to methodA—first step, thereby obtaining a compound represented by the generalformula (VI)

[0082] Method B—First Step

[0083] The amino group of 3-(4-thiazole)alanine synthesized inaccordance with a method described in Synth. Commun., 20, 22, 3507(1990) and Chem. Pharm. Bull., 38, 1, 103 (1990), is protected by aprotecting group for an amino group, such as t-butyloxycarbonyl,benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, phthaloyl,trifluoroacetyl, and the like to obtain a compound represented by ageneral formula (X). This compound and a pyrrolidine derivativesynthesized by a method described in Tetrahedron, 27, 2599 (1971) aresubjected to a peptide bond formation.

[0084] When t-butyloxycarbonyl is used for the protection, theprotecting reaction can be carried out as follows. 3-(4-thiazole)alanineis dissolved in a solvent, such as dioxane, tetrahydrofuran,acetonitrile, and the like. Boc₂O is added to the solution at 0 to 50°C., preferably 10 to 30° C., and stirred for 1 to 5 hours, preferably 2to 4 hours.

[0085] A peptide bond formation can be carried out in a manner similarto that of the above-described method A—First step.

[0086] Method B—Second step

[0087] A deprotecting reaction for an amino group can be carried out asfollows. When the protecting group is t-butyloxycarbonyl, a compoundrepresented by a general formula (XI) is dissolved in a solvent, such asethyl acetate, and the like. 1 to 4 N hydrochloric acid-ethyl acetatesolution is added to that solution at −10 to 30° C., preferably in ice.The resultant mixture is stirred at the same temperature for 1 to 5hours, preferably 2 to 3 hours.

[0088] The resultant deprotected substance can be subjected to a peptidebond formation similar to that of method A—First step, thereby obtaininga compound represented by the general formula (VI).

[0089] In the production method, a compound represented by the generalformula (V-A) or (V-B) is preferably L-threonine or D-threonine(R¹=methyl). Further, compounds represented by the general formulas(VII-A), (VII-B), (II-A), (II-B), (I-A), (I-B), (III-A), (III-B),(IV-A), (IV-B), and (VI) are also preferably compounds derived fromL-threonine or D-threonine.

[0090] As R², benzyl is preferable. As R³ and Y, methyl is preferable.

[0091] In Examples, the following abbreviations are used.

[0092] Me:methyl

[0093] Z:benzyloxycarbonyl

EXAMPLES Example 1

[0094]

[0095] Potassium hydroxide (54.77 g) and a compound (1) (L-threonine)(100.0 g) were dissolved in water (1000 ml). To the solution was addedpotassium carbonate (139.23 g). The resultant solution was cooled below10° C. Toluene (180 ml) solution of Z-Cl (157.5 g) was dropped into thesolution at 10±5° C. for about one hour while the solution wasvigorously stirred. The stirring was further continued for about 1.5hours at the same temperature. Thereafter, the resulting reactionmixture was extracted with toluene (120 ml). The aqueous layer waswashed with toluene (200 ml). Each toluene layer was extracted withwater (50 ml) again. The aqueous layers were combined. To the resultantaqueous layer was added 25% hydrochloric acid (about 294 g) to adjustthe pH to 2.0±5, followed by extraction with ethyl acetate (800 ml). Theorganic layer was washed with 10% brine (400 ml). Each aqueous layer wasextracted with ethyl acetate (200 ml) again. Thereafter, the organiclayers were combined. The organic layer was evaporated. Adding ethylacetate (1000 ml) to the residue and condensing were repeated twice.Further, methanol (500 ml) was added, followed by evaporation.Thereafter methanol was added to adjust the volume to about 440 ml. Tothe resultant methanol solution of compound (2) was dropped thionylchloride (109.9 g) at 10±10° C., followed by stirring at 20±10° C. for2.5 hours. The reaction mixture was dropped into a slurry of sodiumhydrogencarbonate (211.6 g) in water (1320 ml) over about 30 minutes.The resultant slurry was stirred at 5° C. for one hour. Thereafter,crystals were collected by filtration and dried, to obtain 206.3 g ofcompound (3) (yield 92%).

[0096] Melting point: 91° C.

[0097]¹H NMR (CD₃OD) δ 1.19 (d, J=6.38, 3H), 3.73(s, 3H), 4.21-4.31 (m,2H), 5.11 (s, 2H), 7.30-7.38 (m, 5H)

Example 2

[0098]

[0099] A solution of a compound (3) (50.0 g) and thionyl chloride (24.48g) in toluene (250 ml) was stirred at 80° C. for 8 hours and thereafterwas cooled to room temperature. The reaction mixture was extracted withwater (150 ml). The aqueous layer was washed with toluene (25 ml). Eachtoluene layer was extracted with water (50 ml) again. Thereafter, theaqueous layers were combined. 36% hydrochloric acid (18.94 g) was addedto the resultant aqueous layer. The aqueous layer was stirred at 80° C.for one hour and thereafter the water was evaporated. Water (100 ml) wasadded to the residue, followed by condensation. Adding acetonitrile (200ml) to the residue and condensing were repeated three times.Acetonitrile was added to adjust the volume to about 50 ml. Theresultant slurry was stirred at 0±5° C. for one hour. Thereafter,crystals were collected by filtration and dried. Thus, 17.4 g ofcompound(5) was obtained (yield 64%).

[0100] Melting point: 165° C.

[0101]¹H NMR (CD₃OD) δ 1.38 (d, J=6.52, 3H), 4.40 (d, J=8.64, 1H), 4.96(dq, J=6.54, J=8.66, 1H) [α]_(D) ²⁰−19.5° (C=1.0, H₂O)

Example 3

[0102]

[0103] A solution of a compound (3) (3.0 g) and thionyl chloride (1.47g) in toluene (15 ml) was stirred at 80° C. for 8 hours and thereafterwas cooled to room temperature. The reaction mixture was extracted withwater (9 ml). The aqueous layer was washed with toluene (1.5 ml). Eachtoluene layer was extracted with water (3 ml) and water (1.5 ml). Theaqueous layers were combined. The resultant aqueous layer was condensed,thereby obtaining 1.48 g of compound (4) as oil (yield 83%).

[0104]¹H NMR (CD₃OD) δ 1.31(d, J=6.48, 3H), 3.79(s, 3H), 4.46(d, J=8.52,1H), 4.96(dq, J=6.48, J=8.52, 1H)

Example 4

[0105]

[0106] Methanol (5 ml) was added to compound (4) (1.0 g) and-cooled inice. 20% aqueous sodium hydroxide solution (2.5 g) was added to thesolution, which was in turn stirred in ice bath for 30 minutes. 98%sulfuric acid (0.62 g) was added to the solution. Thereafter,precipitated crystals were filtered out and the filtrate was condensed.Adding acetonitrile (5 ml) to the residue and condensing were repeatedfour times. Acetonitrile (8 ml) was added to the resultant residue. Thesolution was dried over anhydrous sodium sulfate (2.2 g). The sodiumsulfate was filtered out and the filtrate was condensed. The resultantslurry was stirred in ice bath for 30 minutes. Thereafter, crystals werecollected by filtration and dried, thereby obtaining 0.50 g of compound(5) (yield 55%).

Example 5

[0107]

[0108] 36% hydrochloric acid (10.5 g) was added to compound (5) (3.00g). The solution was refluxed under stirring for hours. Thereafter,water was evaporated and water (10 ml) was added to the residue,thereafter condensing. The residual oil matter was dissolved in water(10 ml). Aqueous lithium hydroxide solution was added to the solution tobe adjusted to pH 6, followed by evaporation of water. Methanol (8 ml)was added to the resultant solid, followed by stirring at roomtemperature for one hour, thereafter subjected to filtration and dried.Thus, 2.25 g of compound (6) (L-allo-threonine) was obtained (yield91%).

[0109]¹H NMR (D₂O) δ 1.20 (d, J=6.30, 3H), 3.83 (d, J=3.90, 1H), 4.36.(dq, J=3.90, J=6.60, 1H) [α]_(D) ²⁰+9.07° (C=2.0, H₂O)

INDUSTRIAL APPLICABILITY

[0110] According to the production method of the present invention,oxo-oxazoline derivatives and alloamino acid derivatives can be producedin a stereoselective and inexpensive manner.

1. A method for production of a compound represented by the generalformula (I-A) or the general formula (1-B), comprising the step oftreating a compound represented by the general formula (II-A) or thegeneral formula (II-B) with thionyl chloride as follows:

wherein R¹ is an optionally substituted lower alkyl, an optionallysubstituted aryl, an alkynyl, or an optionally substituted heteroaryl;R² is a lower alkyl, an optionally substituted aralkyl, or an optionallysubstituted heteroarylalkyl; and R³ is a lower alkyl.
 2. A method forproduction according to claim 1, wherein the compound represented by thegeneral formula (II-A) or the general formula (II-B) is allowed to reactwith 1.0 to 5.0 equivalents of thionyl chloride in a solvent of toluene,ethyl acetate, cyclohexane, or acetonitrile at 30° C. to reflux.
 3. Amethod for production according to claim 1, wherein the compoundrepresented by the general formula (II-A) or the general formula (II-B)is allowed to react with 1.0 to 3.0 equivalents of thionyl chloride in asolvent of toluene, ethyl acetate, cyclohexane, or acetonitrile at 60°C. to 80° C.
 4. A method for production of a compound represented by thegeneral formula (III-A) or the general formula (III-B), comprising thestep of subjecting a compound represented by the general formula (I-A)or the general formula (I-B) obtained by a method according to any ofclaims 1-3 to a hydrolysis as follows:

wherein R¹ and R ³ are as described above.
 5. A method for production ofa compound represented by the general formula (IV-A) or the generalformula (IV-B), comprising the step of subjecting a compound representedby the general formula (III-A) or the general formula (III-B) obtainedby a method according to claim 4 to a hydrolysis as follows:

wherein R¹ is as described above.
 6. A method for production of acompound represented by the general formula (I-A) or the general formula(I-B), comprising the step of protecting the amino group of a compoundrepresented by the general formula (V-A) or the general formula (V-B)with R²OC(═O)—, wherein R² is as described above, esterifying thecarboxyl group thereof, and treating with thionyl chloride as follows:

wherein R¹ and R³ are as described above.
 7. A method for production ofa compound represented by the general formula (VI):

wherein R¹ is as described above, and Y is an optionally substitutedalkyl, comprising the step of subjecting a compound represented by thegeneral formula (III-A) or the general formula (III-B) obtained by amethod according to claim 4 to a peptide bond formation.
 8. A method forproduction according to claim 4, wherein R¹ is phenyl, 5-imidazolyl,methyl, isopropyl, ethynyl, or 1-propynyl.
 9. A method for productionaccording to claim 4, wherein R² is a lower alkyl, an aralkyl, or aheteroarylalkyl.
 10. A method for production according to claim 4,wherein R² is an aralkyl.
 11. A method for production according to claim4, wherein R¹ is methyl and R² is benzyl.